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At least 253 records · Page 14Linked to original sources
PubMed2003

Split hand foot malformation is associated with a reduced level of Dactylin gene expression.

Split hand foot malformation (SHFM) is a congenital limb malformation presenting with a median cleft of the hand and/or foot, syndactyly and polydactyly. SHFM is genetically heterogeneous with four loci mapped to date. Murine Dactylaplasia (Dac) is phenotypically similar, and it has been mapped to a syntenic region of 10q24, where SHFM3 has been localized. Structural alterations of the gene-encoding dactylin, a constituent of the ubiquitinization pathway, leading to reduced levels of transcript have been identified in Dac. Here, we report a significant decrease of Dactylin transcript in several individuals affected by SHFM. This observation supports a central role for dactylin in the pathogenesis of SHFM.

F-Box Proteins↗
PubMed2002

Cancer/testis antigens: an expanding family of targets for cancer immunotherapy.

Cancer/testis (CT) antigens are a category of tumor antigens with normal expression restricted to male germ cells in the testis but not in adult somatic tissues. In some cases, CT antigens are also expressed in ovary and in trophoblast. In malignancy, this gene regulation is disrupted, resulting in CT antigen expression in a proportion of tumors of various types. Since their initial identification by T-cell epitope cloning, the list of CT antigens has been greatly expanded through serological expression cloning (SEREX) and differential mRNA expression analysis, and approximately 20 CT antigens or antigen families have been identified to date. Characteristics commonly shared by CT antigens, aside from the highly tissue-restricted expression profile, include existence as multigene families, frequent mapping to chromosome X, heterogeneous protein expression in cancer, likely correlation with tumor progression, induction of expression by hypomethylation and/or histone acetylation, and immunogenicity in cancer patients. Spontaneous humoral and cell-mediated immune responses have been demonstrated against several CT antigens, including NY-ESO-1, MAGE-A, and SSX antigens. Since CT antigens are immunogenic and highly restricted to tumors, their discovery has led directly to the development of antigen-specific cancer vaccines, and clinical trials with MAGE-A and NY-ESO-1 are in progress.

Antigens, Neoplasm↗
PubMed1996

Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes.

Pfeiffer syndrome (PS; McKusick MIM 101,600) is an autosomal dominant craniosynostosis syndrome with characteristic craniofacial anomalies and broad thumbs and big toes. We have previously demonstrated genetic heterogeneity in PS and mapped a gene to chromosome 8 (ref. 3) and a second to chromosome 10 (ref. 4). The gene on chromosome 8 is the fibroblast growth factor receptor 1 (FGFR1) with a common mutation (C755G) predicting a Pro252Arg substitution. The gene on chromosome 10 is FGFR2 with several different mutations causing sporadic and familial PS (Table 1). We report a recurrent single point mutation in the FGFR3 gene, located on chromosome 4p, in ten unrelated families with craniosynostosis syndromes. This mutation (C749G) predicts a Pro250Arg amino acid substitution in the extracellular domain of the FGFR3 protein. Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively.

Acrocephalosyndactylia↗
PubMed2006

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Abnormalities, Multiple↗
PubMed2006

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Adolescent↗
PubMed1997

Polymorphism and structure of the gene coding for the alpha 1 subunit of the Artemia franciscana Na/K-ATPase.

Genomic clones coding for one of the two identified Artemia franciscana Na/K-ATPase alpha subunits, the alpha 1 subunit, have been isolated. Several overlapping clones were obtained, although their restriction maps showed a large heterogeneity. Sequencing of their exons showed that they differ in up to 3.46% of their nucleotides in translated regions and 8.18% in untranslated regions. Southern blot analysis of DNA purified from different lots of A. franciscana cysts and from isolated individuals suggests that the variation is due to the existence of multiple Na/K-ATPase alpha 1 subunit alleles in A. franciscana. The Na/K-ATPase alpha 1 subunit gene is divided into 15 exons. Ten of the 14 introns are located in identical positions in this gene as in the human Na/K-ATPase alpha 3 subunit gene. Analysis of the 5' flanking region of the gene has allowed identification of the transcription-initiation sites. The adjacent upstream region has been shown to have functional promoter activity in cultured mammalian cells, suggesting the evolutionary conservation of some of the promoter regulatory sequences.

Amino Acid Sequence↗
PubMed2002

Towards identification of genes in regionally accumulated strabismus.

Strabismus, as an inherited disease, is a new challenge to the geneticist. Various forms of strabismus can be found in distantly related members of the same family, who usually report to local ophthalmologists and orthoptic centers very rarely. In addition, local ophthalmologists and orthoptic centers very rarely pay attention to the genetic aspects of strabismus. Therefore, the recruitment of suitable families to identify the underlying genes is the major drawback in this effort. Further problems arise from the mode of inheritance, which can formally be characterized as autosomal dominant with reduced penetrance in most families, but should be considered as multifactorial inheritance with a threshold combination of mutated alleles. The present paper deals with a method for using local accumulations of strabismus patients to circumvent the problems of small families and rare numbers of affected persons. The steps on the way to the identification of strabismus genes will be described.

Chromosome Mapping↗
PubMed2006

Determination of heterogeneous thermal parameters using ultrasound induced heating and MR thermal mapping.

In this paper, a method for the determination of spatially varying thermal conductivity and perfusion coefficients of tissue is proposed. The temperature evolution in tissue is modelled with the Pennes bioheat equation. The main motivation here is a model-based optimal control for ultrasound surgery, in which the tissue properties are needed when the treatment is planned. The overview of the method is as follows. The same ultrasound transducers, which are eventually used for the treatment, are used to inflict small temperature changes in tissue. This temperature evolution is monitored using MR thermal imaging, and the tissue properties are then estimated on the basis of these measurements. Furthermore, an approach to choose transducer excitations for the determination procedure is also considered. The purpose of this paper is to introduce a method and therefore simulations are used to verify the method. Furthermore, computations are accomplished in a 2D spatial domain.

Body Temperature↗
PubMed2005

A Greek family with a follicular variant of familial papillary thyroid carcinoma: TCO, MNG1, fPTC/PRN, and NMTC1 excluded as susceptibility loci.

The familial form of nonmedullary thyroid carcinoma (FNMTC) has been recognized as a distinct clinical entity and is characterized by multifocality and a more severe phenotype than its sporadic counterpart. The majority of FNMTC pedigrees are small in size, show variable modes of inheritance, and may present with a variety of additional benign thyroid disorders. The existence of marked phenotypic differences between FNMTC families suggests that there is genetic heterogeneity. Recent studies have mapped a susceptibility locus for FNMTC at 2q21. This locus appears particular relevant to families with at least one case of the follicular variant of papillary thyroid cancer (fvPTC). We describe the clinical and pathologic characteristics of a large three-generation fPTC kindred, with two of the four PTC patients presented with the follicular variant of PTC. It is of interest the occurrence of PTC in three siblings within a period of 3 years. In addition, multinodular goiter (MNG) was diagnosed in seven individuals, lymphocytic thyroiditis in four, while one diagnosed with a benign adenoma. From the PTC patients, one had MNG and fvPTC, one MNG, lymphocytic thyroiditis and papillary pattern of PTC, one lymphocytic thyroiditis and fvPTC, and one MNG and papillary pattern of PTC. The inheritance pattern was autosomal dominant with incomplete penetrance and women were affected more frequently than men. Considering all PTC-affected individuals, the limit of detection (LOD) score we got for this family on 2q21 was 0.5. The low LOD score is caused by a PTC patient who does not share the affected haplotype, suggesting that maybe a new locus for PTC predisposition is present in this kindred. Linkage analysis also excluded TCO, MNG, and fPTC/PRN as susceptibility loci to FNMTC in this family.

Adenocarcinoma, Follicular↗
PubMed2003

Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15.

Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.

Charcot-Marie-Tooth Disease↗
PubMed2006

Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring.

Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.

Chromatin↗
PubMed1994

Single indicator of risk for schizophrenia: probable fact or likely myth?

The longitudinal followup strategy in high-risk research is being increasingly complemented by the use of psychosis-proneness scales to select subjects for study who might be vulnerable to schizophrenia and who show differences on laboratory measures that could act as endophenotypic markers for use in genetic investigations. Three types of experimental paradigm have been adopted, drawn from cognitive psychology, psychophysiology, and the neuropsychology of hemisphere function. Results adopting each of these approaches are examined, alongside recent factor-analytic evidence that psychosis-proneness scales currently in use tap up to four different components that map onto the clinical heterogeneity of schizophrenia (and possibly other forms of psychosis). No one of these components clearly emerges as, or points to, a single indicator of risk, though some aspect of neurocognitive functioning seems a likely candidate. Even so, it is argued, the clinical expression of vulnerability must be due to a convergence in an individual of several components of risk since individually (and notably so for "susceptibility to positive symptoms") they are very common in the healthy population. In evaluating the evidence, attention is drawn to two crucially different ways that investigators in schizophrenia research have construed the notion of continuity (1) as subclinical defect (or forme fruste of disease) having varying expression or (2) as biologically based personality dimensions that simultaneously describe the dispositions to aberrations of function leading to degree of illness. It is noted that the model of continuity chosen can significantly shape the way the results of risk research are interpreted and the theories of psychosis to which they give rise.

Genetic Markers↗
PubMed1992

Vaccinia virus gene SalF5R is non-essential for virus replication in vitro and in vivo.

A gene designated SalF5R from within the SalI F fragment of vaccinia virus strain WR has been characterized. The predicted primary translation product has 194 amino acids with an Mr of 22578 and has features typical of a class I membrane glycoprotein. At the amino and carboxy termini there are runs of hydrophobic residues that might function as membrane signal and anchor sequences, respectively, and after the C-terminal hydrophobic sequence there is a short charged sequence that may prevent passage of the molecule through the membrane. Between these hydrophobic regions there are two potential sites for addition of N-linked carbohydrate. Northern blotting using a probe to an internal region of the open reading frame (ORF) detected an early transcript of 750 nucleotides and late transcripts of heterogeneous length. However, accurate mapping of the 5' ends of these transcripts did not reveal a monocistronic mRNA that might allow translation of the full-length SalF5R ORF. Instead two early transcripts were found, one beginning 130 nucleotides downstream of the start of the ORF, and a second initiating in the short intergenic region between SalF5R and SalF6R. The nearest late initiation site mapped to the beginning of the upstream gene SalF4R (profilin) and not the beginning of the SalF5R ORF. A virus deletion mutant lacking an internal 554 nucleotides of the 582 bp SalF5R ORF was constructed by insertion of the Escherichia coli guanine phosphoribosyl transferase gene linked to the vaccinia virus p7.5K promoter. The rate of replication and the final titre of intracellular naked virus produced by this virus was indistinguishable from wild-type virus in CV-1 and RK13 cells. In intranasally infected mice the virus lacking SalF5R was not attenuated in comparison to wild-type virus. The SalF5R site may be useful for insertion of foreign DNA into recombinant vaccinia viruses.

Administration, Intranasal↗
PubMed2003

Microbeam synchrotron imaging of hairs from ancient Egyptian mummies.

Developments in microfocus synchrotron techniques have led to new results regarding the long-term alteration of archaeological samples of biological origin. Here, ancient hair samples from two Egyptian mummies have been analyzed using a conjunction of structural and elemental synchrotron methods. In this favored context of conservation, structural analysis revealed a remarkable preservation of keratin supramolecular organization at any observed length scale. Bulk keratin structure has therefore not been modified significantly over 2000 years. However, infrared spectroscopy indicated a partial disorganization of keratins close to the hair surface through polypeptide bond breakage. Elemental mapping showed a strongly heterogeneous distribution which can be related to mummification and cosmetic treatments.

Archaeology↗
PubMed1994

Epitope mapping with synthetic peptides of 52-kD SSA/Ro protein reveals heterogeneous antibody profiles in human autoimmune sera.

The reactivity of autoantibodies present in the sera of 489 patients with Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and other autoimmune diseases was investigated by ELISA using recombinant 52-kD SSA/Ro protein (rRo52) and 39 overlapping synthetic peptides representing the entire sequence of Ro52. We report that IgG antibodies reacting with rRo52 were present in the sera of a large number of patients with SS (67% of patients with primary SS and 46% of patients with SS associated with SLE), whereas they were less frequent (10-25%) in SLE, rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and mixed connective tissue disease (MCTD), and absent in scleroderma. Among the 39 peptides tested, five were recognized by sera from 30-65% of patients with SS, namely peptides representing residues 2-11, 107-122, 107-126, 277-292 and 365-382. Patients with JCA had raised levels of IgG antibodies reacting with peptides 2-11 and 365-382, and 51% of patients with MCTD had raised levels of IgG antibodies reacting with peptide 365-382. None of the five peptides was recognized by more than 20% of sera from patients with SLE and RA. Interestingly, and of importance in the field of diagnostic tests based on peptides, the reactivity of antibodies to the Ro52 synthetic peptides varied greatly according to the origin of sera. Inhibition experiments using either patients' sera or antibodies induced in rabbits against Ro52 peptides showed that the four domains 2-11, 107-122, 277-292 and 365-382 are accessible on the surface of the Ro52 protein. These regions may thus be involved in the induction of specific antibodies in autoimmune patients.

Amino Acid Sequence↗
PubMed2006

A novel SCN2A mutation in family with benign familial infantile seizures.

Benign familial infantile seizures (BFIS) is a clinical entity characterized by focal seizures with or without secondary generalization, occurring mostly in clusters, and usually first seen between 4 and 8 months of life. Psychomotor development is normal, and seizures usually resolve within the first year of life. BFIS is a genetically heterogenous condition with loci mapped to chromosomes 19 and 16. Mutations in the voltage-gated sodium channel alpha2 subunit (SCN2A) gene on chromosome 2 were recently identified in families affected by neonatal and infantile seizures (benign familial neonatal-infantile seizures, BFNIS) with typical onset before 4 months of life. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS show overlapping clinical features. We report a pedigree showing three affected individuals over three generations. All subjects experienced clusters of focal seizures with or without secondary generalization and onset between 4 and 12 months of life. Response to antiepileptic drugs and the outcome were good. No subjects had other forms of epilepsy later in the life. Neonatal or febrile seizures did not occur in the family. Genetic study in this family revealed a novel heterozygous mutation c.3003 T>A in the SCN2A gene. Comparative analysis of different sodium channel alpha subunits indicates that the mutated residue is highly conserved throughout the evolution, suggesting an important functional role for this domain. Additional families with the infantile form of benign familial seizures should be investigated to corroborate that BFIS and BFNIS may share the same genetic abnormality.

Age of Onset↗
PubMed1985

Simian agent 12 is a BK virus-like papovavirus which replicates in monkey cells.

We have begun to characterize the genomic structure and replication of the baboon papovavirus simian agent 12 (SA12). We have defined a wild-type clone of SA12 (SA12 wt100) by plaque purification from a heterogeneous stock. The functional map of SA12 wt100 can be aligned with those of the other primate papovaviruses by assigning one of the two EcoRI sites as 0/1.0 map units. The origin of bidirectional viral DNA replication maps near 0.67 map units, consistent with the limits of sequences homologous to origin sequences in the other papovaviruses. DNA sequence analysis shows that the organization of the SA12 genome is similar to that of the other primate papovaviruses studied. The arrangement and sequence of functional elements in the origin of replication region, as well as the sequences of the N-terminal regions of early protein products, indicate that SA12 is most closely related to the human virus BK, next most closely related to JC virus, and less closely related to simian virus 40. Unlike BK virus, SA12 is capable of productive infection of African green monkey kidney cells.

Animals↗